Physiological regulation of immune responses is a fundamental mechanism of limiting autoimmune disease. The cellular basis for a defect underlying autoimmune disease remains under investigation. Recent data from animal models demonstrate that CD4+CD25+ T cells play a major role in regulating autoimmune diseases, particularly diabetes in the NOD mouse. Thus, the CD4+CD25+ T cell may be the long sought-after regulatory T cell, a defect in which underlies human autoimmune disease. The recent identification of CD4+CD25+ Tcell may be the long sought-after regulatory T cell, a defect in which underlies human autoimmune disease. The recent identification of CD4+CD25+ regulatory cells in the circulation of normal humans that exhibit identical in vitro characteristics to the CD4+CD25+ regulatory cells isolated in mice is the basis for the coordinated U-19 Program Project Grant. This U-19 program project is a focused effort of five laboratories: the Fathman Laboratory at Stanford, the Weiner Laboratory at Harvard, the Eisenbarth Laboratory at the Harbara Davis Diabetes Center in Denver, the Khoury and the Hafler laboratories also at Harvard to determine: the mechanism of action of regulatory CD4+CD24+ T cells in models of autoimmune disease, and whether they can be induced by experimental interventions. We will determine whether there are defects in these CD4+CD25+ regulatory T cells in human autoimmune disease, and define the mechanisms of these defects. We will focus on two autoimmune diseases, type 1 diabetes and multiple sclerosis. The fundamental hypothesis for this grant application is that a defect in the number of the CD4+CD25+ regulatory cells or their regulatory function in patients with type I diabetes or multiple sclerosis underlies the dysregulation of the immune system in these diseases. Correction of this potential defect provides a novel approach for prevention of human autoimmune disease. This Program exemplifies the most fundamental concept of a BASIC/CLINICAL PROGRAM PROJECT since all three projects are highly interdependent. It is through the interrelationship between projects that we wish to rapidly transfer technology from the bench to the understanding and development of human autoimmune diseases.